CA1262552A

CA1262552A - LONG-CHAIN .alpha.,.omega.-DICARBOXYLIC ACIDS AND DERIVATIVES THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

Info

Publication number: CA1262552A
Application number: CA000484907A
Authority: CA
Inventors: Jacob Bar-Tana; Ernst-Christian Witte; Bernd Hagenbruch; Johannes Pill; Karlheinz Stegmeier
Original assignee: Yissum Research Development Co of Hebrew University of Jerusalem
Current assignee: Syndromex Ltd
Priority date: 1984-06-22
Filing date: 1985-06-21
Publication date: 1989-10-31
Also published as: NO860661L; WO1986000298A1; DK75986A; GR851509B; EP0185080A1; EP0185080B1; ES544439A0; AU4607185A; HUT38892A; DE3574130D1; ES8604090A1; US4711896A; JPS61502537A; DE3423166A1; FI860711A0; DD240541A5; IL75549A0; DK75986D0; ZA854684B; FI860711A

Abstract

ABSTRACT

Long-chain .alpha.,.omega.-dicarboxylic acids of formula I' I' and in vivo hydrolyzable functional derivatives of the carboxylic groups thereof, wherein R1 and R2 each independently represents lower alkyl;
lower alkyl substituted by hydroxy, lower alkoxy, halogen or phenyl which may be substituted one or more times by hydroxy, lower alkoxy, lower alkyl or halogen; lower alkenyl; lower alkynyl; C3 - C7 cycloalkyl; phenyl or phenyl substituted by hydroxy, halogen, lower alkyl or lower alkoxy; X and Y indepen-dently represents hydrogen, lower alkyl, lower alkoxy, cyano, halogen carboxyl, lower alkoxy-carbonyl, carbamoyl or hydroxy and Q represents a linear, satu-rated or unsaturated alkylene chain of 8 to 14 carbon atoms which may be -(a) substituted by oxygen, halogen, hydroxy or lower alkoxy, (b) interrupted by one or more heteroatoms and/or (c) of which 1 - 4 chain members may be part of a C3 - C7 cycloalkyl or phenyl ring pro-vided that when Q represents a linear saturated alkylene chain of 8 to 14 carbon atoms, R1 and R2 represents methyl and Y hydrogen, then X is not hydrogen, ethoxycarbonyl, bromo, cyano or methyl or when R1 and R2 represents methyl, X and Y are hydrogen, then Q is not the group

Description

~ int. Nr. 2671 Long-cnain ~-dicarboxylic acids, procesS for tne preparation thereoL and pnarmaceutical com~ositions containin& them Subject of EP-OS 0 081 930 are some long-chain ~,G~-dicarboxylic acids of formula I

. ~ ~1 R1 X
H~OC - C - C - Q - C - C - COOH (I~

~: 'X R2 R2 Y
~ .
and in-vivo hydrolysable functional derivatives of the carboxylic groups thereof, wherein and R2 each independently represents ~n unsubstituted or substituted hydrocarbyl ox heterocyclyl radical;
20 X and Y each independently represents hydrogen, optionally substituted lower alkyl, halogen, cyano, carboxy, lower alkoxycarbonyl or carbamoyl; and 25 Q r~presents a diradical consisting of a linear chain of 8 to 14 carbon atoms, one or more of which may be replaced by heteroatoms, said chain being optionally substitute~ by inert substituents and one or more o~ said carbon or : 30 heteroatom chain members optionally forming part of a ring : structure;
' ,~r These compounds are useful as medicaments for the treatment o~
o~esity, nyperlipidemia and diaDetes.

:' ' . , ~
1000 11.83 Sb,:

.,.
.

5 5~

In this patent application there are only examplified ~hose compounds of formula I, wherein X represen~s hydrogen9 etnoxycarDonyl, bromo, cyano or methyl, Y respresents hydrogen, ~1 5 and R2 each represents metnyl and Q represents -(CH2)10 ~ or -(CH2)12- groups.
Now it was found tnat numerous compounds which fall under th~ broad scope of tne vague terms o~ ~ormula I o~ EP-OS 0 081 930 and which 10 are not disclosed therein provide a significant lipid-lowering effect and aaaitionally an antidiabetic effect.

Tne pr~sent invention is concerned with long-cnain ~,6a --dicarboxylic acias o~ ~ormula I' X R ~ X
,1 ,1 ~OOG - C - C - Q - C - C - COOH I' 20y ~2 R2 Y

ana in vivo nydrolyzable functional aerivatives of tne carboxylic groups thereof, wnerein Rl and ~2 each independently represents lower alkyl; lower alKyl suhstituted by hydroxy, lower alkoxy, halogen or phenyl which may be su~stituted one or more times by nydroxy, lower al~oxy, lower al~yl or halogen; lower alkenyl; lower alkynyl;
C3 - C7 cycloal~yl; phenyl or pnenyl su~stituted by hydroxy, n31Ogen, lower al~yl or lower alkoxy;

:

1000 11.83Sb.

X and Y each independently represents hydrogen, lower al~yl, lower alkoxy, cyano, halogen, carboxyl, lower alkoxy-carbonyl, carbamoyl or hydroxy and Q represents a linear, saturated or unsaturated alkylene cnain o~ 8 to 14 carDon atoms wnich may be ~ (a) substitut~ ~y oxygen~ halogen, hydroxy or lower alkoxy, : (~) interrupted ~y one or more neteroatoms and/or (c) ot wnich 1 - 4 cnain members may be part of a C3 - C7 cycloal~yl or pnenyl ring provided tnat when Q represents a linear saturated alkylene cnain o~ B to 14 car~on atoms, Rl and R~ represents methyl and Y nyarogen, then X is not hydrogen~ ethoxycarbonyl, bromo, cyano or rnethyl or when Rl and ~2 represents met~yl, and X and Y are hydrogen, then Q is not tne group -CH2-CH2- ~ -CH -C~ -20A known compound is 1,4-phenylene-bis-(3,3-dimethyl-~-yl-pentanoic acid), described by A.T. Blomquist et al ( J.A.C.S.
80 (195~ 3405), b~lt no pharmaceutical utility is disclosed.
Lower alkyl groups suitable as the substi-tuents Rl, R2, X and Y are group with 1-6, especially 1-4 carbon atoms: preferred are methyl and ethylO Lower alkoxy groups ~uitable a~ the sub~tituentA R1~ R2, X and Y as well as as s~bstituents in Q are groups o~ 1 - 6, e~pecially 1-4 carbon atoms: methoxy and ethoxy are preferred. Lower alkoxy carbonyl groups of subqtitu~nt~
:~ X and Y are suitably group~ with 1-6 carbon atoms, preferred among ~hich are ~ethoxy-carbonyl and ethoxy carbonyl.
Lower alkenyl groups ~uitable as the ~ubstit-~ uents Rl and R2 contain 2-6 c~rbon atoms: preferred is ;~ : allyl. Lower alkynyl groupB ~uitable 29 the substit-uent~ Rl and R2 contain 2-6 carbon atoms, and preferred ~, is propynyl~ Halogen mean~ in all case~ fluorine, 5b; chlorine and bromine.
:: .

~'~6~

Phenyl can be substituted in all case~ by ; hydroxy, lower alkoxy (Cl-C6), lo~er alkyl (Cl-C6) or halogen. Lower alkyl group~ which are ~ubg~ituted by phenyl are preferably benzyl and phenethyl, whereby the phenyl gro~tps can be 3ubstituted by the above mentioned ~ubstituentctO Cycloalkyl group~ (C3-C7) of ~bcttituents Rl and R2 and a~ part of Q are preferably cyclopropyl, cyclohexyl and cycloheptyl.
10The group Q is usually con~tructed 3ymmetri-~ally because of the 3ynthesis thereof. Preferred are re~îdues aq -(CH2)8-, -(CH~)lo~ (CH2)12 2 14 Preferred unsaturated chain~ are -(CH2)4-CH=CH-(CH2)4-and -(CH2)5-CH=CH-(CH2)5-. A chain Q can be 9ub~tituted by oxygen, e.~. containing a keto-qroup.
Preferable is the residue -(C1~2)2-JI-(CH2)4 tl (CH~)2 O O
The groupt can alqo be interrupted one or more timeY by heteroatoms consisting of oxygen, sulphur or nitrogen which may be ~tbstituted by lower alkyl (Cl-C5) or benzyl. The sulphur atom~ can be oxidized to SO or SO2. The following groups are preferred:

2)5 (CH2)5 ; ~(CH2)5-S-(CH2)5-;
-(CH )5-N-(CH2)5-~ -(CH2)2 5 ( 2 4 2 2 ~H3 A ring 9y~tem can preferably be part of a chain Q. This ring ~ystem can be ~aturated (cycloalkylidene) or un3aturated (phenylen~). Preferred cycloalkylidene ring sy~tem~ are cyclopropylidene and cyclohexylidene, which are located at the 1~1-; 1,2 ; 1,3- or 1,4- position, e.g. (CH2)4-cyclopropylidene or cyclohexylidene-(CH2)4~. The number of carbon atom~ of the total chain i~ in ca~e of the 1,1 and 1,3-connection uneven~ Thi~ applies alqo to chains which are interrupted by one hetero atom. A phenyl rinq ~ may be inserted in 1,2-; 1,3-or 1,4-poctitiort in the :
I~ It~ Sb.

.

i255~

chain, e.g.:
-(CH2)3-phenylene-(CH2)3-;
-(CH2)4~phenylene-(CH2)4-;
-CH2-CH=CH-phenylene-CH=CH-C~12-; or -CH2-CH=CH-CH2-phenylene-CH2-CH=CH-CH2-.
From all above mentioned chains Q the followln~
meanings of the substituents ~1' R2r X and Y are preferred: Rl and R2, each independently methyl, ethyl, hydroxymethyl or phenyl, X and Y independently hydrogen, halogen, methoxy, hydroxy, ethoxycarbonyl, cyano, carbamoyl or carboxyl; especially Rl and R2 methyl, X and Y hydrogen or Y = hydrogen and X = halogen, ethoxycarbonyl, hydroxy, methoxy, cyanot carbamoyl or carboxyl.
Included within the scope of the invention are those derivatives of the ~ -and/or ~'-carboxy groups of the compounds oE formula I above, which are capable of being hydrolyzed in-vivo to yield the free diacids of formula I. Among such suitable derivatives there should be mentioned, in: the first place, salts with pharmaceutically acceptable inorganic or organic cations, in par-ticular alkali metal salts, alkaline earth metal salts, ammonium sal-ts and subs-tituted ammonium salts; esters, particu-larly lower alkyl esters, e.g. methyl, ethyl and isopropyl esters; amides, mono- ancl di-alkylated amides, e.g. a dimethylamide or lactones formed by ring closure of either or both carboxylic groups with a free hydroxy substituent (or substituents) in the molecule of formula (I').
~: Subject of the invention are also cis/trans isomers of the unsaturated compounds.

: ,.

, ~ .

' The novel compoundqi of formula (I) accor~ing 1 to the invention, can be prepared by method~ known per 3e, some of which ~re illu~trated in the examples here-in. Compoundci of fo~mula I can be prepared in known manner by a) transferring a dihalogen compound of for-mula VIII

Hal- Q-Hal (VIII).
in which Hal mean~ chlorin~ or bromine and Q has the sa~e meaning aqi above, in a bi~-Grignard compound and reacting, the obtained compound with two mols of a com-; pound of formula III
R300C~ ,R1 C ~ C (III) ;~
in which Rl and R~ have the ~ame meaning a3 above, R3 :~ repre3ents a lower alkyl group and U i9 a COOR3-group or : a -CON~2 or CN group, or ~ .
whereupon, if desired, the obtained compound is saponified, ;~ if desired is decarboxylated and if desired the substituents ~ 25 alkyl, alkoxy, hydroxy or halogen are introduced in ~- and ; ~ -position `~ or in case, when X and Y repr~sent hydrogen, halogen, hydroxy~
~ alkyl or alkoxy, : 30 i b) by reacting a bi~-tripheny1phosphonium compound of formula IV
'' :~ 35 Z tPh)3 P ~ Ql P (Ph)3 (IV), ~`'', .. .
1000 11.83 Sb.

:, ~ 7 - ~X~552 ~ 1 in whlch j z is chloride or bromide, and o1.is a linear, saturated or un~aturated alkylene chain with 2-12 carbon atoms, which may be aa) qub~tituted by oxygen, halogen, hydroxy or lower alkoxy) bb) interrupted by one or more h~teroatomR
and/or cc) of which up to 4 members of the linear chain can be part of a C3-C7 cycloalkyl or a phenyl ring, with 2 mols of carboxylic acid ester of formula V

R OOC-CH -C-Q -CH=O (V), in which Rl and R2 have the same meaning a~ above, R3 repre~ent~
a lower alkyl group and ~2 is a valency bond or an I alkylene chain with up to 5 carbon atom~, with the provi-qo that in the reaction product Ql and two Q2 together do not form a chain consi ting of le3s than 8 carbon atoms or more than 14 carbon atoms, wPIereupon in the compounds obtained with X and Y = hydrogen f desired the substituents alkyl, alkoxy, halogen or hydroxy are introduced in ~- and ~ -position, , whereupon ~he c~ pounds obtained of formula I' may be convert~d to other compound~ of formula I',, and obtained e3ters, amides or ~a~ts may be converted into I their free acids, or ree acids may be converted into `' ~alts, eqters or amides.
~j 35 Process a) u~ually leads to tetrae~terq.
These compounds may be hydrolyzed by al~ali and subse-~j quently decarboxylated by heating~ The resulting com-pounds wi~h X, Y - hy~rogen may be halogenated in the ~position. ThiY ~an be done by direct ~luorination, iOO~ 11.83 Sb.

8 ~ s~

bromination or chloronation or by the appropriate halogen N-succinimide.

~,~ -Difluoro-compounds may be also obtained by reaction of the corresponding ~ dichloro-compounds with tetrabutylammonium fluoride. Alkyl groups are normally introduced after reaction with e.g. n-butyl lithium by means of the corresponding alkyl halides.~,G~ -Hydroxy-compounds can be obtained e.g. by saponification of the corresponding dichloro compounds with alkali.
Alkoxy groups can be introduced in d,~ -position by reaction of the corresponding dichloro compounds with alcoholates (e.g. sodium methylate).

According to process a) there can be obtained dioic esters with a cyano or carbamoyl substituent in ~ and G~-position.
The cyano group if desired can be saponified to a carbamoyl group and further to a carboxy group. The carbamoyl groups if desired can be dehydrated to a cyano group in known manner.

; According to process b) only compounds with X and Y = hydrogen are obtained.

Generally the bis-phosphonium salt of formula IV reacts with 2 mols of carboxylic acid ester of formula V in the presence of strong bases, e.g. NaOH or sodium methylate, whereby there results a diester of an at least doubl~ unsaturated Q chain.
The residue Q1 may substituted, interrupted or part of a ring system analogous to Q. Instead of the bis-phosphonium salt of ` formula IV appropriate phosphine oxides or phosphonic acid -~
esters may be used.
i i 35 ~, ' ,, lOoO 1~ ISb.

9 1.~5$~

1 Proces~ b) can be u~ed preEerably to obtain compo~nds with a re~idue Q which containY a phenylene or cycloalkylidene radi~ or i~ interrupted by hetero atoms.
The re~ulting unqaturated compounds may be hydrogenated sub~equently to the corre3ponding saturated compound~.
Analogou31y, phenylene compound~ may be hydrogenated to cyclohexylidene compounds.
The phenylene or cycloalkylidene compounds may al~o be pepared by reacting a compound of ~ormula Vl Me/2-(cH2~q~A-(cH2)q-Me/2 (VI), in which Me i3 a divalent metal, e.g. cadmium or zinc A i~ phenylene or C3-C7 cycloalkylidene and q ;9 1 or 2, with a compound of formula VII
Rl T-(CH2) -C-CH2COOAlkyl (VII), in which T is an active carboxyclic acid residue, e.g.
acid halide or acid anhydride, and R1,Rz and q have the same meaning as above, and 3ubaequently if de~ired hydrolyzing the requlti~g diketo-e~ter3 and reducin~ the keto groups.
The olefines may be obtained by using as ~trong ba~e~ alkali-metal alcoholate~, e.g. lithium or ~odium methylate: alkali amide , e.g. sodium amide: or organo-metallic (e.g. lithium) compounds, e.g. n-butyl lithium or sod;um hydride. The reaction medium is preferably a lower alcohol or an ether e.g. diethylether or tetrahydrofuran.

1000 tl.~

' "
- ' .
.

55~

1 ~he hydr~g~n~tion of th~ bis alkene resulting fro~ proc~sq b) occurs under u~ual conditions in the presenc~ of metal catalyst9, e.g. palladium/charcoal at normal pressure preferred are u~e of pres~ure greater than atmo~pheric and tempe~ature above ambient.
Useful catalyqts for the hydrogenation of the phenyl ring are platinum, rhodium or rutheniu~. Keto groups of diketo acids or esters resulting in proce~s a) are reduced preferably analogou-~ly to the ~uang-Minlon-proces~ (heating a mixture consisting of a ketone, di-luted alkali, glycol and hydraZine~ or by the Clemmensen reduction (in the presence of zinc or copper containing zinc and hydrochloric acid). It i9 also possible to convert the keto compounds into tosyl hydro-azones Which are gubsequently reduced by complex al~ali metal boron hydrides.

Esters of the free acids according to formula I' are obtaine~
in usual manner e.g. reacting the free acid with thionyl chloride to give`the acid chloride and further reacting with a suitable alcohol.
Esters can be saponified in usual manner by alkali in an alcohol.ic solution, but also in an acid medium, i.e. with a mix-ture of concentrated sulphuric acid and oleum~

Pharmacologically acceptable salts are especially alkali metal, alkaline earth metal and ammonillm sa]ts. They are obtained in the usual manner, for example, by neutralising compounds of general formula (I) with suit able bases or acids. For the preparation of pharma-ceutical compositions, the compounds of general formula (I) are mixed in known manner with appropriate pharma-ceutical carrier substances, aroma, flavouring andcolouring materials and formed, for example, into tablets or dragees or, with the addition of appropriate adjuvants, suspended or dissolved in water or an oil, for example, olive oil.

.

:' , ,. ~ .

5~i~

The compounds of general formula (I) can be administered orally and parenterally in liquid or solid ~orm. AS injection medium, i-t is preferred to use water which contains the stabilising agents, solubilising agents and/or buf~ers conventional for injection solutions. ~dditives of this kind includ~, for example, tartrate and borate buffers, ethanol, dimethyl sulphoxide, complex formers (such as ethylenediamine-tetraacetic acid), high molecular weigh~ polymers ~such as liquid poly-ethylene oxide) for viscosity regulation and poly-ethylene clerivat:ives o~ sorbitan anhydrides.
Solid carrier materials can be, for example, starch, lactose, mannitol, methyl cellulose, talc, ;~ highly dispersed silicic acid and high molecular weight polymers (such as polyethylene glycols).
::
` Composi~ions suitable for oral administration can, if desired, contain flavouring and/or sweetening agents. For external use, the compounds of general formula (I) according to the present invention can also be used in the ~orm of powders and salves.
For this purpose, they are mixed, for example, ~ with powdered, physiologically compatible diluents ; or conventional salve bases.

:
;~, ~25iS~

The dosage administered depends upon the age, -the state of health and ~he weight of the recipien~, upon the extent of the disease, the nature of possibly simultaneously administered other treatments, the frequency of the treatment and the nature of the desired effect. Usually the daily dosage of the active compound is from 0.1 to 50 mg./kg. of body weight. Normally, 0.5 to 40 and preferably 1.0 to 20 mg./kg./day in one or more administrations per day are effective in order to obtain the desired results.

'~

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Test report Compounds of Examples 3 and 6c) of ~he invention were tested in respect to a lipid-lowering effect in comparison to the best compound of EP-OS 81.930, the 3.3.14.14-tetramethyl-hexadecane~1,16-dioic acid (M 16).

Groups of 10 male Sprague-Dawley rats were given the test substance orally for 29 days at a dosage of 50 mg/kg/d and 50Q mg/kg/d in the form of a methyl cellulose suspensionO At the end of the experimental period and 3 hours after the last administration, the cholesterol and triglyceride valu,es in the serum were determined. The changes were determined in comparision with controls.

substance cholesterol- triglycerides-mg/kg/d sinking (%) sinking (%~

Ex. 3 50 31 51 Fx. 6c)50 42 51 25 ~ 500 62 66 M 16 50 24 4~

Apart from t~e compounds described in the examples, preferred compounds according to the present invention include the ~ollowing:

' ,~
~: w~
1000 11.83 Sb.

"
"' ~":

2~iiS~

1) 2,3,3,14,14,15-hexa~ethyl-hexadecane-1,16-dioic acid 2) 2,15-di-carba~oyl-3,3,14,14,-tetramethyl-hexadecane-1~16-dioic acid 33 3,14-diethyl-3,14-dimethyl-hexadecane-1,16 ~i~ic acid

3,3,14,14-tetra-(2-propenyl)-hexadecane-1,16-dioic acid 5) 3,3,14,14-tetra cyclohexyl-hexadecane-1,16 dioic acid 6) 2,15-dibromo-3,3,14,14-tetraphenyl-hexadecane-1,16 dioic acid 7) 1,2-cyclopropylîdene-biq-(3,3-dimethyl-7-yl-heptanoic acid) 15 8) 9,9-pentamethylene-3,3,15,15-tetramethyl-heptadecane-1,17-dioic acid 9) 1,2-cyclohexylidene-bis-(3,3-dimethyl-7-yl-heptanoic acid) lO) 1,2-phenylene-bis-(3,3-di~ethyl-7-yl-heptanoic 20 acid) 11) 3,3,15,15-tetramethyl-9-thia-heptadecane-1,17-dioic acid 12) 9-oxa-3,3,15,15-tetramethy~-heptadecane-1,17-dioic acid 25 13) 9-aza-3,3.9,15,15-penta~ethyl-heptadecane-1,17 dioic acid 14) 3,3,14,14-tetramethyl-6,11~thia-hexadecane 1,16 dioic acid 15) 2,15-difluoro-3,3,14,14-tetramethyl- :
hexadecane-1,16-dioic acid :~ 16~ 2,2,15,15-tetrafluoro-3,3,14,14-tetramethyl-hexadecane-1,16-dioic acid ; 17) 2,2jl5,15-tetrachloro-3,3,14,14-tetramethyl-:~ 35 hexadecane-1,16-dioic acid :~ .
lODO ~ .,~13 Sb.

. ' : ` "': ':' lB) 2,2,15,15-tetrafluoro-3,3,14,14-tetramethyl-hexadecane-1,16-dioic acid 19) ~,3,14,14-tetrahydroxymethyl-11,16-d.ioic acid 20) 2,15-dichloro-3,14-di(chloromethyl)-3,14-dimethyl-hexadecane-1,16 dioic acid 21) 2,15-dichloro-3,3,14,14-tetra (chloromethyl)-hexadecane-1,16-dioic acid 22) 3,3,14,14-tetra-(4-hydroxyphenyl)-hexadecane-1,16-dioic ~cid 23) 3,3,14,14-tetra-(4-chlorophenyl)-hexadecane-1,16-dioic acid 24) 3,3,14,14-Tetra-(4-methyl-phenyl)-hexadecane-1,16-dioic acid 25~ 3,3,14,14-tetra (4-methoxy-phenyl)-hexadecane-1,16-dioic acid : 30 ~ , : 35 ~, ' .
1000 1 r.~3 8b .

.~ :
: " : .
,':'; ~ ` -~25~a~
~XAMPLE 1 -1,4-ph ny~ene-bis-[(~ di~ethyl-but-4-yl)-di~-opionic acid dime~hyl e3ter]

A Gr~gnard 901ution produced from 3.3 9 magne-sium turnings, 2~,0 g (62.5 mmol~ 1,4--bis-(3-bromo-propyl)-benzene ~nd 150 ml absolute tetrahydrofuran i9 added dropwiqe to a ~olution consi~ting of 25.6 g (124 mmol) isopropylidene malonic acid diethylester at -20C

and is subsequently kept for 2 - 3 hours at reflux temp-erature~ The cooled mixture i~ poured into acidified ice water. The aqueous phase is separated off, ex-tracted twice with ether and the combined organic phase is waqhed with sodium carbonate sol~tion, dried with Na2S04 and evaporated. The residue left after eva-poration is heated at 0.01 bar to about 150~C to re~ove volatile secondary prod~cts and there remains 23.6 g (67 theoretical y;eld) of a vi~cous oil. Purification of a small amount of a srnall amount by means of HPLC gave a viscous oil that had an T1C-precoated Merck silica gel 60/F 254 plates of 0.8 in n-heptane-ethyl acetate 1:1 and of 0.5 in n-heptane-ethyl acetate 2:1.

NMR (DDMS0): ~ = 1.02 (s, 12H); 1.12 (tr, 12H~; 1.40 (m, 4H);

3.30 (s, 2H); 4.07 (qu, 8H); 7.03 (m, 4H).

--1,4-phenylene-bis-t(l,l-dimethyl-but-4-yl)-dipropionic acid)]
_ .

A mixture con~isting of 2.5 g (4.4 mmol) of the tetraethyl ester from example 1, 25 ml methanol and 1.0 g (25 mmol) ~odium hydroxide are heated under reflux for 60 houre, then cooled, water i3 added and e~traction with ether car~ied out. The mixture is then aciclified and the acid initially separtes as an oil~
After crystallization, the material is fil-tered off ~ washed with water and dried. Yield 1.8 g ~90% of the theoretical): melting point 181 - 183C
~with decornpositlon)0 NMR (DDMSO): f = 1.03 (s, 12H): 1.40 - 1.60 (m, 8H), 2.48 (m, 4H); 3.12 (3, 2H); 7.07 (~, 4H) ~000 11.B3 Sb.

. ' ~

-1,4~phenylene-bis-(3,3-dimethyl-6-yl-hexanoic acid_ The named product i3 obtain~d by heating 1.4-phenylene-bis-[(l,l-dimethyl-but-4-yl)-dipropionic acid]
(example ~ ) for 2 hour~ under nitrogen at 160C.
Yield 31 ~ of the theoretical: melting point 119 - 121C ~cyclohexane) NMR tDDMSo): ~ = 0.93 (s, 12H); 1.30 (m, 4H);
1.53 (m, 4H), 2.08 (~, 4H), 2.49 (t, 4H);
7.067 (4H).

EXAMP~E 4 a) 1,4-phenylene-bi~-(3,3-dimethyl-6-yl-S-hexenoic acid methyl e~ter) A 30dium methylate solution prepared from 0.92 g (40 mg atom) sodium and 50 ml absolute methanol is added dropwise to a mixture consisting of 6.3 g (40 mmol) 3,3-dimethyl-S-oxopentanoic acid methyl ester, 60 ml absolute methanol and 14.0 g (20 mmol) 1-,4-pheny-lene-bis-(methyltriphenyl-phosphonium chloride) at room temperature, and the mixture is stirred for 3 hours at room temperature and then evaporated. The residue is dissolved in methylene chloride, filtered and again evaporated. After column chromatography (to remove a ~mall quantity of fluorescent material) u3ing CH2C12/~ilica gel, 3.8 9 (49 ~ of the theoretical yield) of a colorles~ oil i~ obtained.
Isomeric mixture NMR (CDC13~: 1.02 (12 H); 2.00 - 2.55 (8 H);
3.58 and 3.63 (6 H), 5.23 -6.83 (4 H), 7.27 (4 H) IDOO 11.~ ~b.

i2~
~ - 18 -b) l,3-~henylen~-bi~-(3!3=dimethyl-6-yl-5-hexenoic acid methyl ester) This compound is obtained in a manner analo~
gous to Example 4a) from 3,3-dimethyl-5-oxo-pentanoic acid methyl ester and 1,3-phenylene-bis-(methyltri-phenyl-phosphonium chloride).
Yield 60 % of the theoretical; oily product I~omeric mixture NMR (CDC13): J = l.oS (12 H); 2.15 - 2.~0 (8 H);
3.58 and 3.67 (6 H), 5.25 - 6.73 (4 H), 7.23 (4 H) a) 1,4-phenylene-bis-(3,3-dimethyl-6-yl-hexanoic acid methyl ester) A mixture consisting of 2.0 9 1,4-pehnylene-bis-(3,3-dimethyl-6-yl-5-hexenoic acid methyl ester) from Example 4a, S0 ml ethanol and a spatula tip of 10 Pd on charcoal catalyst is ~d~nat~ in a shaking ap-paratus at normal pressure until completion of the hy-drogen uptake. After filtering off the catalyst, the solution i~ evaporated and 1.5 9 (74~ of the thoretical yield~ of a colorle~s oil is obtained.
NMR (CDC13)~ ~ = 0.97 (3, 12 H); 1.17 - 1.78 (m, 8 H) 2.17 (s, 4H): 2~37 - 2.70 (m, 4 H~, 3.60 (s, 4 H), 7.07 (s, 4 H) 1000 11.l.~ '`b.

. ' ~;
.:
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b) 1,3-phen~lene-bi~-(3,3-dimeth~-o-~-hexanoic acid methyl e~ter) l This compound i~ obtained in a manner analo-goue~ to Ex~mple 5a) by hydrogenation of 1" 3-phenylene--bi3-(3,3-dimethyl-6-yl-hexenoic acid methyl e~ter), example 4b)-Yield ~4 ~ of the the~retical; colorle~s oil.
NMR (CDCl3~:J = 0.98 (9, 12 H); l.lQ - 1.93 (~, 8 H);
2.20 (s, 4H), 2.38 - 2.73 (m, 4 H): 3.63 (6 H):
6.83 - 7.23 (m, 4 H) .
a) l!4~phenylene-bi3-(3,3 dimethyl-6-yl-hexanoic acid) A mixture consi~ting of 0.5 g of the methyl ester (ex~mpie 5a ), 5 ml ~ethanol ~nd 5 ml 2 N-NaOH is heated for 3 hours at 90~C, then the methanol is di~-lS tilled off, water i~ added and the mixture i~ extracte~
with ether. The aqueou~ pha~e i9 then acidified and extracted with ether, and the ether extract dried with N~2SO4. After evaporation 0.4 9 (86% of the theoretical yield) of a product with a melting point 120 -121C
(cyclohexane) is obtained. The product is identical to that obtained according to example 3.
b~ l,3-phenylene-bis-(3,3-dimethyl-6-yl-hexanoic acid) This compound i~ obtained in a manner analo-gous to Example ~) by hydroly3is of its methyl ester (example Sb).
Yield 9l~ of the theoretical; colorle~s oil.
NMR ~DDMSO~: J= 0.93 (~, 12 H) 1.30 (m, 4 H), 1.53 (m, 4 H); 2.07 (s, 4 H), 2.49 (t, 4 H) 6.92 - 7.00 (m, 3 H); 7.15 (t, l H).
c) ~,4-phenylene-bis-~3~3-dimethyl-6-yl-5-hexenoic acid This compound is obtained in a manner analogous to example 6a) by hydrolysis of its methyl ester (Example 4a).
Yield 67 ~ of the theoretical; melting point 149-151C
~acetone);mixture of isomers.
NMR (DDM50): d-= 1.00 (s, 12H); 2.10 (s, 4H); 2.38 (mr 4H);
5.47-5.92 (m~ 2H); 6.24-6.57 (m, 2H);
7.27 (m, 4H).
10~0 11.~ Sb, ;.

~ ~i25i5~

d) 1,3-phenylene-bis-(3,3 dimethyl-6-yl-5-hexenoic acicl) 1 This compound is obtained in a man~er analogous to ex~mple 6a) by hydrolysis of its methyl ester (example 4b).
Yield 91 % of the theoretical; colourless oil, nD20 = 1.5433 mixture of isomers.
NMR (DDMSOj: ~ = 1.00 (s, 12H); 2.13 (s, 4H); 2.22-2.50 (rn, 4H) 5.5-5.95 (m, 2H); 6.22-6.65 (m, 2H);
7.18 ~m, 4H).
~XA~P~E 7 a) 1,4-cyclohe~ider.~-bi~-~3,3-dimethyl-6~ hexanoie - acid methyl e~ter) A mixture co.~*isting of 3.7 9 1,4-L~henylene-bi3-(3,3-dimethyl-6-yl-.exanoic acid-methyl e~ter), ex~n-ple 5a) and a 50 ~1 methanol are hydrogenated in the : 15 presence of ruthenium !IV) oxide at 90C and 80 bar.
The solution is then filtered and evaporated.
Yield 0.7 g (98~ of the theoretical); color-le~s oil.
. NMR tCDC13):S = 0.97 (~, 12 H): 1.10 - 150 (m, 22 H), ; 20 2.18 (s, 4 H), 3.65 (6 H) b~ 1,3-cyclohexylidene-bis-(3,3-dimethyl-6-yl-hexanoic acid methyl e3terL
In a similar way, the named compound iq ob-tained fro~ the corresponding 1,3-phenylene analog.
Yield 69~ of the theoretical, of a colorless oil.
NMR (CDC13)~ = 0.98 (~, 12 H), 1.07 - 1.88 (m, 22 H):
2.20 (5, 4 H). 3.65 (9, 6 ~).

a~ 1,4-cy~lohexylidene-bis-~3,3-dimethy~ yl-hexanoic acid) The named compound i obtained by hyd~oly~is o~ the methyl e~ter (example 1a ) in analogy to example 6a ).
Yield 76~ oÇ the theoreti~al: melting point 167 - 169'C (ethyl acetate)~
NMR (DDMS~): S = Q.94 (~ 2 H): 1.06 - 1.76 (I~l, 22 H);
2.07 ~, 4 ~) 000 l,i .~3 Sb.

`, . :
~'~

1 b) 1,3-cyclohexylid~ne-bis-(3,3-dimethyl-6-yl-hexanoic acid) Simil~rly t~lis compound is obtained from the compound of example 7~ ).
Yield 89% of the theoretical; melting point 74 - ~6C (ethyl acetate3 N~R (DDMS0):~ = 0.94 (s, 12 H) l.Oh - 1.76 ~m, 22 H):
2.~6 (s ~ ~) EXAMPL~ 9 1,4~phenylene-bis-(3,3-dime~hyl-7-y~-5-he~tenolc ~cid) a) ',A-phenylene-bis-~ethy'triphenyl~phosphonil.~ bro-mide) A mixture consisting of 5.84 9 (20.H mmol), 1,4-bi~-2-(bromethyl)-benzene and 13.1 g (50.~ mmol) triphenyl phosphine i3 heated under N2-atmosphere for 15 mins. to 220C, and then for 30 mins. at 2~n-'`. The solidified crude product nbtained on cooling i~ recry-stallized from ethanol: there i~ obtained 6.6 ~ (40~) of a colorless crystalline material with a melting point of 262 -263C.
b) 1,4-phenylene-bis-(3,3-dimethyl-7-yl-5-heptenoic acid) 21 ml of a 1.2 mol solution of n-butyl-lithium in hexane is added to a stirred suspension of 8.17 g (10.0 mmol) 1,4-phenylene-bis-(ethyltriphe~yl phos-phonium bromide) in 300 ml anhydrous ether at room tem-perature under N2- atmosphere and the mixture is stirred or a 15 min, a~ter which a solution of 2.65 9 (20.0 mmol) 3,3-dimethyl S-oxo-pentanoic acid methyl ester in ' 10 ml ether is added dropwise and the mixture is then heated subsequently for 2 hours under reflux.
After cooling the precipitate is filtered off, ~` the filtrate is concentrated and the oily residue i9 taken up in ~0 ml 1 N gOH and 10 ml ethanol and is heated for 2 hours to 50C. The volume is then reduced ; to a half and the mixture i~ extracted several time~
with dichloromethane. The aqueous phase i~ acidified .83 Sb.
- ~

, : ~ .

- 2~ 55;~

with 2 N HCl and extracted several timeq ~ith dichloro-1 methane. The oil obtained after drying and evaporation of the organic phase is bro~ght to crystallization with ligroin. 1.0 g (26% of the theoretical yield) of a colorless crystalline material with the melting point of 78- 80C is obtained.
NMR (DDMS0):~ = 0~99 (3, 12 ~); 2.13 (c, 4 H), 2.17 (d,J=7.2Hz; 4 ~I), 3.33 (d,J=6.9 Hz: 4 H) 5.50-5.64 (m, 4 H): 7.08 (s, 4 H) EXAMFL~ 10 1,3-phenylene-bis-(3,3-dimerhyl-7-yl-5-hepten~ cid) a) l,3-phenylene-bi~-tethyltriphenyl phosphorlium bro-mide) is obtained analogou~ly to example 9a) ~rorn 1,3-bi~-(2-bromethyl)-benzene and triphenylphosphine.
Yield ~2% of the theoretical, colo~7e~s cry-stal~: melting point 219 - 220~C (methanol)~
b) 1,3-phenylene-bi~-(3,3-dimethyl-7-yl-5~heptenoic acid) is obtained analogol~sly to example 9b) using 1,3-; phenylene-bis-(ethyltriphenyl phosphonium bromidel.
Yield: 51~ of the theoretical; colorless oil, nD26 = 1.5202--Rf = 0.55 (DC-late~ ~lerck 60/toluene-dioxanne-acetic acid 90:25:10) or 0.27 (n-heptane-ethyl acetate 1:1).

a) 1,4-ehenylene-bis-(3,3-dimethyl-7-yl-heptanoic acid) iq obtained from 1,4-phenylene~bis-(3,3-dimethyl-7-yl-5-heptenoic acid), example 9 by normal pressure hydrogena-tion u~ing palladium as the catalyst.
Yield 52% of the theoretical, melting point ; NMR (CDC13): S = 1.00 (~, 12 R); 1027 - 1.47 (m, 12 H), 2.20 (s, 4 H), 2.47 - 2.73 (m, 4 H), 7.08 (s, 4 ~).
~, ~', ' .
11.83 Sb.

5~

b) 1,3~phenylene-bis-(3,3-dimethyl-7-yl-heptanoic acid) is obtained analogously.
Yield 41% of the theoretical; colorless crystals, melting point 63-64C~
NMR (CDC13): ~ = 1.00 (s, 12 H); 1.27 - 1.8Q (m, 12 H);
2.22 (s, 4 H); 2.43 - 2.77 (m, 4 H);
6.87 - 7.20 (m, 4 H).

By hydrogenation of the corresponding 1,4-phenylene-bis-acid or the 1,3~phenylene-bis-acid on rhodium contact one obtains in analogy to example 7.
a) 1,4-cyclohexylidene-bis-(3,3-dimethyl-7-yl-hep-tanoic acid).
Yield: 72% of the theoretical; colorless oil.
NMR (CDC13: i - 0.77-1.85 (m, 26 H); 1.02 (s, 12 ~I);
2~22 (s, 4 ~I).
b) 1,3-cyclohex~lidene-bis-(3,3-di_e-thyl-7-yl-hep-tanoic ac_d).
Yield 66~ of the theoretical Melting point: 52-55C (water) NMR (CDC13): cJ= 0.80-1.80 (m, 26 H); 1.02 (s, 12 H);
2.23 (s, 4 H).

. . ._. .
1,4-phenylene-bis-(3,3-dimethyl-S-oxo-7-yl-hepkanoic acid).
14.6 g (50.0 mmol) 1,4-bis-(2-bromo-ethyl)-benzene in 100 ml anhydrous ether is dropped on to 2.40 g (0.10 g atom) magnesium turnings with ; stirring, so that the reaction mixture boils. On completion of the addition, the mixture is heated under reflux for 1.5 hours, is cooled and then 10.1 g (55.0 mmol) cadmium chloride are rapidly added.
The mixture is again heated under reflux for 45 min., and then distilled off and 100 ml benzene is added to the reaction mixture. The suspension thus obtained is added with vigorous stirring to a 55~

solution of 17.3 g (50.0 mmol) 3,3-dimethyl glutaric acid methyl es-ter chloride in 25 ml benzene, is heated for 45 min under reflux, cooled and decomposed by -the addition of 2N H2SO4. The crude product obtained after separation, drying and reduction o~ the organic phase is dissolved in 100 ml ethanol and 100 ml lN KOH and heated for 8 hours at 60C.
Subsequently, the volume is reduced to half, is extracted several times with ether and acidified with 2N HCl. The aqueous phase is then extracted several times with ether, and the combined extracts are dried and evapora-ted. The residual oil is crystallized in ligroin/ether. 4.1 g (20~ of the theoretical) colorless crystals with a melting point of 116-120C (isopropanol).
NMR (CDC13): ~ = 1.06 (s, 12 H); 2.55 (s, broad;
8 H); 2.50-3.00 (m, 8 H); 7.03 (s, 4 H).

1,4-phenylene-bis-(3,3-dimethyl-7-yl-heptanoic acid) A mixture consisting of 1.05 g (2.50- mmol) 1,4-phenylene-bis-(3,3-dimethyl-5-oxo-7-yl-heptanoic acid), e~ample 37, 1.00 g (17.0 mmol) potassium hydroxide and 1.03 g (20.0 mmol) hydrazine hydrate is heated in 10 ml die-thylene glycol for 2 hours under reflux, then for 5 hours, at 200C -to distill off the water. Subsequently, the mixture is cooled and poured into 70 ml water and acidified with diluted hydrochloric acid. The mixture is stirred for hour and the precipitate is collected.
0.60 g ~61%) colorless crystals with a melting point of 118-120C (toluene).
The compound is identical to that obtained according to Example lla.

~' .

~.

5~

2,15-dichloro-3,3,14,14-tetrameth~lhexadecane-1,16-dioic a _ 0.128 g of 3~3,l4~l4-tetramethylhexadecane-1,16-dioic acid prepared as described in EP-OS 81 930 was dis~olved in 2 ml of SOC12. The mixture was refluxed for 2 h followed by the addition of 2 ml of SOC12 and 0~162 g of N-chlorosuccinimide (NCS)~ The mixture was further refluxed for 4 1/2 more hours, evaporated to dryness and the crude product was di~olved in CC14 and filtered. The filtrate wa~ evaporated to dryness and the crude bis-(alpha chloroacid-chloride) was subjected to silicic acid chromatography with petrol ether as eluent. 87% yield.
NMR (CDC13): 4.46 (s, 2H); 1.34 (m, 20H) 1.00 (s, 6H): 0.97 (s, 6H).
The bi~-(alpha-chloroacid chloride) wa~ hydro-lyzed quantitatively by boiling with water for 16 h.
The reaction mixture was then extracted with chloroform and the chloroform extract was dried over anhydrou3 magnesium sulfate, filtered and evaporated to dryne~s to yield the crude title compound. The crude product was di~olved in bicarbonate solution, acidified to pH 2.0, and extracted with chloroform. The chlorofor~ extract was dried over anhvdrous magnesium ~ul~ate, evaporated ; to drynes~ and was further dried in high vacuum for 24 h. The solidifed product wa~ cry~talizad ~rom petrol ether. m.p. 103-112C.
NMR (CDC13): 4.17 (g, 2H) 1.26 (m, 20~), 1.00 (9, 12H).
Analy~ %C 58.12 (Calc. 58.38) ~H 8.70 (Calc. 8.82 .

1000 ` J83 Sb.

55~

-2,15-dihydroxy 3~3~l4~l4-tetramethylhexadecane-l~l6 dioic acid -0.2 g of 2,15-dichloro-3,3,14,14-tetra~ethyl-hexadecane-1,16-dioyl chloride prepared a~ described in Example 15 wa~ di~olved in 10 ml of 30% KOH ~olution.
The mixture wa~ boiled for 3 h, cooled and acidified to pH 2Ø The precipitate was collected by filtration and dissolved in ethyl acetate. It cry~talized upon adding petrol ether. m.p. 87-100C. 61% yield.
NMR (CDC13): 3.90 (s, 2H); 1.13 (m, 20H), 0.90 (s, 12H).
Analy3is: ~C 64.24 (Calc. 64.17), ~H 10.15 (Calc. 10.16).

ExAMpLE 17 1,14-di-(carbomethoxy)-1,14-dichloro-~,2,13,13 tetra-_ .
methyltetradecane 1.23 9 of 1,15-dichloro-3,3,14,14-tetramethyl-hexadecane~l,16-dioylchloride prepared as described in Example 15 wa~ dissolved in 50 ml of ab~olute methanol.
The mixture waR refluxed for 16 h, then evaporated to dryness and the crude product wa~ dissolved in chloro-form. The chloroform pha~e was waYhed with bicarbonate solution, water, dried over anhydrous magneqium sulfate and was evaporated to dryness. 40~ yield.
NMR ~CDC13)~ 4.15(~, 2H):3.70 (s, 6H):
1~20H); 1.05 (s, 12H).
.

ICOO ~3 Sb.

"~ ''-' , "' ,:
:' , :' ' ~, 5~

= ~

dioic acid 1.21 g of 2,15-dibromo-3,3,14,14-tetramethyl-hexadecane-1,16-dioic acid prepared as described in EP-OS 81.930 was dissolved in 50 ml of methanol con~aining 0.58 g of ~odium methoxide. Containing the addition of 64 ml of H2O the mixture was heated 2~t 60C for 4 days.
The solvent was then evaporated to dryness and the crude product was dissolved in water, washed with ether, acidified by HCl and extracted into ether. The ether extract wa3 dried over anhydrous magnesium sulfate and was evaporated to drynes~ to yield the title compound.
61~ yield.
NMR (CDC13): 3.47 (s, 2H); 3.39 (s, 6H): 1.24 (m, 20H); 0.95 (d, 12~
IR: 3000, 1712, 1120 cm Analysis: ~C 65.51 (Calc. 65.67); ~H 10.60 (Calc. 10.45).

3,3,14,14-tetramethyl-8-hexadecane-1,16-dioic acid 40 g of dimedone was dissolved in 60 ml of 20%
KOH solution followed by the addition of 33 g of 1,4-dibromobutene, 1.4 g of copper powder prepared by thereduction of CuO and 14 ml of 20% KOH solution. The mixture was ~tirred for 4 d followed by di~solvin~ the ::~
.
. ~

~' 35 i, 1 ~olidlfied product in 10~ NaOH~ The ba~ic solution waa filtered, the filtrate was extr~ted with ether and acidified to precipitate the 1,4~bis-dimedone-2-butene condensation product. 1,4-bis-dimedone-2-butene wa~
crystallized from acetone. m.p. 205-206C.
NMR (DMSO): 5.20 (m, 2H~; 2.72 (m, 4H), 2.20 (s, 8H): 1.025 (~, 6H).
Analy~is: ~C 72.29 (calc. 72012): ~H 8.43 (calc. 8.69).
Ma~s ~pectro~copy: molecular ion - 332.
8.0 9 of 1,4-bis-dimedone-2-butene, 6 ml of 85% hydrazine hydrate and 5 ml of methanol were added to a solution of 5 g NaOH in 50 ml of triethyleneglycol The mixture wa~ heated at 120C for 36 h, then heated to 195C with the evaporation of water followed by reflux for 20 h. The mixture wa~ cooled, diluted with water, extracted with ether, acidified and extracted into CH2C12. The dichloromethane extract was wa~hed with water, dried over anhydrous magnesium sulfate, eva-porated to dryne3s and further purlfied by silicic acid chromatography in 20:1 dichloroethane:methanol to yield the title compound. The title compound was crystalized from petrol ether. m.p. 100-lOl~C.
NMR (CDC13~: 5.38 (quint, 2H): 1.99 (~, 4H);
1.31 (m, 12H); 1.01 (s, 12H).
Analysi3: %C 70.54 (Calc. 70.59): %H 10.78 (Calc. 10.59).

~,3,14,14-tetraphenyl-6,11-diketohexadecane-1,16-dioic 3~ acid The bis-Grignard reagent prepared from 0.49 9 of 1,4-dibromobutane and 0.7 9 of Mg turnings in 15 ml of dry THF was added dropwise to a stirred suspension of 2.0 9 of 4,4-diphenylcyclohexanone [J. Org. Chem., 28, 2544~, (1968)] in 20 ml of dry THF. The reaction mixture wa~ refluxed for 16 h, cooled, poured into a mixture of ;', IOGO 11.~3 ~ ,.

: . .

~25~

1 hydrochlor~c ~c~d and ice, then diluted with water ~nd extracted ~ith diethylether. The ether extract wa3 ~a~hed with ~ater, dried over anhydrou~ magne~iu~
~ulfate and evaporated to drynes~ to yield 1,4-bis (4,4-diphenyl-l-cyclohexanol)-butane.
NMR (CDC13) 7.08-7 36 (m, 20H~; 2.38 (m, 8H) 1.55 (m, 8H); 1.23 (m, 8H).
0.5 g of 1,4-bis(4,4-diphenyl-1-cyclohexanol~-butane was dissolved in 40 ml of acetic acid followed by the addition of 3.0 9 of CrO3 in ~mall portions. The mixture was kept at room temperatur~ for 16 hl was then poured on ice, and this was followed by extraction with ether. The ether extract wa~ extracted with sodiu~
bicarbonate qolution, and the latter acidified and ex-tracted with ether. The extract waq dried over anhy-drous maynesium sul~ate and evaporated to dryness to yield the title compound. 50~ yield.
NMR (CDC13): 9.90 (br. s, 2H); 7.13 (m, 20H); 1.9-3.0 (m, 20H).

3,3,14,14-tetraDhenvlhexadecane-1,16-dioic acid .
0.27 g of 3,3,14,14-tetraphenyl-6, ll-diketo-hexadecane-1,16-dioic acid prepared a3 described in Example 20 and 0.23 ml of 85% hydrazine hydrate were added to a solution of 0.4 g KOH in 10 ml of triethy-leneglycol~ The mixture wa3 heated at 120C for 24 h, then heated to 195C with the evaporation of water followed by reflux for 7 h. The mixture wa~ cooled, diluted with water, extracted with ether, acidified and extracted into ether. The ether extract was washed with wa~er, dried over anhydrous magnesium sulfate and evaporated to dryne~s to yield the title compound~ 58 yield.
NMR ~CDC13): 9.7 (~, 2H); 7.16 (~, 20H); 3005 (s, 4H): 1.2-2.6 (m, ~OH).
IR: 3050; 1700 cm 10~0 11.83 Sb.

: .

55;~

Example 22 5 2.15-Di~luoro-3,3,14,14-tetramethyl-1,16-nexadecanedioic aci_ A mixture of 9,2 g (29mmol) tetrabutylammonium fluoride and 3.4 g ~6.4 mmol) of 2,15-di~romo-3,3~14,14-tetrametnyl-1,6-hexadecan~edioic 10 acid was stirred for 48 h at 60 C. Excess water was added and the organic material was extracted with dichlorometnane. The organic solution was washed with water, dried on magnesium sulfate and the solvent evaporated. Tne residue was dissolved in 50 ml of a~solute methanol containing 0.6 ml of concentrated su1furic acid. Tne 15 mlxture was re~luxed for 16 n. Removal of the metnanol in vacuo follo~ed ~y neutralization witn 5 % aqueous so~ium bicar~onate af~oraea 2.U g of crude dimetnyl ester. Column cnromatograpny on silica gel (a mixture of 10 ~ of ether and 90 % of hexane served as eluen~) gave tne pure ester.
N~ CDC13): ~ = 0.959 (d, 6H); 0.957 ~dl 6H); 1.294 (m, 20H);
3.776 (s, 6 H); 4.615 (d, 2 Hg jH-F = 43.8 ;Hz) A mixture of 2,5 g (7,9 mmol~ o~ tetra~utylammonium fluoride 25 trinydrate and 120 mg (0,296 mmol) of the above diester was stirred under argon for lb n at 60 C. Excess water was added and -the organic material extracted witn ether. Tne organic solution was driea on magnesium sulfate and tne solvent removed in vacuo. Tlle resultlng colorless material was recrystallized twice from hexine 3~ containing a small amount of dicnloromethane to yield 42 mg ~38 ~) of ~ne colorless dicarboxylic acid, mp 96-9~.

NM~ (Cl)C13): ~ = 1.024 (s, 6H); 1.031 (s, 6H); 1.251 ~m, 20H);

4-643 ~d~ 2H~ JH F = 48.6 Hz); 7.350 (s, br~ ~H) 1000 ~' '# Sb.
;

~' ',~ ' ' ~ , :

, :: ~ ....

_ 3~ _~ 5 Example 23

5 ~iiso ro 1 2 15-dichloro-3,3,14,14-tetrametnylhexadecane-1,16-dioate P PY _ _ Tne preparation of 2,15-dicnloro-3,3,14,14-tetramethylhexadecane-1,16-dioyl chloride 10 tnrougn ~C12 and oG-cnlorlnation tnrough NCS of the corresponding acid was carried out according to Example 15. Into a st:;rred solutlon o~ tne diacidcnloride in CC14 20 mL of isopropanol was a~de~ at 0 C an~ tnen tne reaction mixture was stirred at roosn ternperature for 48 hrs. Evaporation of the solvent and excess 3f the 15 alconol gave a residue tnat was dissolved in CHC13, washed wit~
water, aq. NaHC03 and water and dried (Na2S04). A$ter rotavaporization o~ the solvent tne residue was purified by flasn chromatograpny (silica gel with gradient CH2C12 in hexane)~

20 Yiela: 6~ ~ o~ tneoretical an~ 20 ~ of the trichloro derivative.

NI~R (CDC13): ~ = 1.01 (s, 12~); 1.22 (s, b, 20H); 1.26 (d, 12H);
4.18 ~s, 2~); 5.01 (septett, 2H) Example 24 2,2,15,15-Tetrachloro-3,3,14,14-tetramethylhexadecane-1,16-dioic acid : Into a tnree nec~ed flasK~ capped with a rubber septum a solution ofU.612 g (6,1 mmol) of dry diisopropylamine in 20 mL dry THF was added under N~. After cooling to 0-4 C a solution of : n-butyllithium in hexane (4.489 mL, 6,1mmol) was injected slowly witn a syringe. Stirring was continued in an ice batn of 30 min then tOO~ Sb.

~2~2~52 the reaction ~ixture was c~oled down to -78 C. and a solution of 1,5 g, (3.03 mmol) Diisopropyl 2,15-dichloro-3,3,14,14-tetramethyl-hexadecane-1,16-dioate in dry THF (15 mL) was added dropwise, with a syringe. This mixture was sitrred at -78 C.
for 30 min (it became bright yellow), and then dry CC14 (3.0 mL , excess) was added dropwise. The yellow color changed into brown. The reaction mixture was allowed to warm up slowly and le~t overnight at room temperature. After cooling to O~C., a 3N HC1 solution was added to pH 1. the THF was evaporated (vacuum), CH2 C12 and water were added and the organic layer was washed with water, aq. NaHC03 and water.
After drying (Na~ S04) and solvent evaporation the crude reslaue was puri~ied by ~lasn cnromatograpny on silica gel ancl ~ gra~lellt o~ C~2~12 in nexane as eluen~.

Ylela: 57 ~ o~ tneoretlcal of tne tetracnloro isopropyl ester, as a colorless oll.

NI~IR ~CDC13): ~ = 1.1~ (s, ~, ZOH); 1.23 (s, 18H) 1.35 (s, 6H);
5.~3 (septett, 2H) Tne titel compound was prepared ~y dropping an ice cold mixture of l : l w/w concentrated sulpnuric acid and oleum (lO g) under cooling to tne pulverized diester, stirring ~or lO minutes in an ice Dath and ad~ing furtner portions of tne mixture sulphuric acid/oleum until tne diester was dissolved. The reaction mixture was cooled to -78 C ana ice and dicnloromethane was added. After dissolution of tne lce, tne organic layer was separated, tne water layer extracted wltn dicnlorometnane and ~ne com~ined organic layers were wasned wltn water and driea over sodium ~icar~onat. Evaporation of tne solvent g ï ves the title compound.

Yiel 7~ ~ o~ theoretical, m.p: 154-154.5~ C (cyclohexane).

.
1~00 ll.llqlSb.

:: ., .. , .. , ,~., ' .

~' . .
.

Claims

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for the preparation of an .alpha.,.omega.-dicarboxylic acid of formula (I'):

I' and in vivo hydrolyzable functional derivatives thereof at the carboxylic group, thereof in which R1 and R2 are the same or different and are selected from the group consisting of lower alkyl; lower alkyl substituted by a substituent selected from hydroxy, lower alkoxy, halogen, phenyl and phenyl itself substituted one or more times by a substi-tuent selected from hydroxy, lower alkoxy, lower alkyl and halogen; lower alkenyl; lower alkynyl;
C3 - C7 cycloalkyl; phenyl; phenyl substituted by a substituent selected from hydroxy, halogen, lower alkyl and lower alkoxy; X and Y, which may be the same or different, are selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, hydroxy, cyano, halogen, carboxyl, lower alkoxycarbonyl and carbamoyl, and Q is a linear, saturated or unsaturated alkylene chain of 8 to 14 carbon atoms, said alkylene chain being:
(a) unsubstituted or substituted by oxygen, halogen, hydroxy or lower alkoxy, (b) uninterrupted or interrupted by one or more heteroatoms, (c) completely uncyclized or having 1 - 4 chain members part of a C3 - C7 cycloalkyl or phenyl ring, provided that when Q is a linear saturated alkylene chain of 8 to 14 carbon atoms, R1 and R2 are both methyl and Y is hydrogen, X is other than hydrogen, ethoxycarbonyl, bromo, cyano or methyl, and provided that when R1 and R2 are both methyl and X and Y are both hydrogen, Q is other than a group of formula:

and pharmaceutically acceptable in vivo hydrolyzable functional derivatives thereof at the carboxylic acid group selected from salts, amides and esters thereof, comprising:
a) forming a bis-Grignard compound from a dihalogen compound of formula (II):
Hal - Q - Hal (II) in which Hal is chlorine or bromine and Q is as defined above, and reacting the bis-Grignard compound with a compound of formula (III):

(III) in which R1 and R2 are as defined above, R3 is lower alkyl and U is a COOR3 group or a -CONH2 or CN group, and, if desired, the product is subjected to one or more processes selected from:

i) saponification or hydrolysis to provide the free acid (I'), ii) decarboxylation to produce a different compound (I'), iii) introducing a substituent selected from alkyl, alkoxy, hydroxy and halogen in the .alpha. - and .omega. -positions, and iv) dehydrating a carbamoyl group to a cyano group; or b) when X and Y are hydrogen, halogen, hydroxy, alkyl or alkoxy, reacting a bis-triphenyl-phosphonium compound of formula (IV):

? (Ph)3 ? - Q1 - ? (Ph)3 ? (IV) in which Z is chloride or bromide, and Q1 is a linear, saturated or unsaturated alkylene chain with 2 to 12 carbon atoms which is:
i) unsubstituted or substituted by oxygen, halogen, hydroxy or lower alkoxy, ii) uninterrupted or interruped by one or more heteroatoms, and iii) completely uncyclized or having 1 - 4 chain members part of a C3 - C7 cycloalkyl or phenyl ring, with a carboxylic acid ester of formula (V):

(V) in which R1 and R2 are as defined above, R3 is a lower alkyl group and Q2 is a valency bond or an alkylene chain with up to 5 carbon atoms, provided that in the reaction product Q1 and Q2 together do not form a chain consisting of less than 8 or more than 14 carbon atoms, and if desired, introducing a substitutent selected from alkyl, alkoxy, halogen and hydroxy in the .alpha.- and .omega.-positions of a compound (I') in which X and Y are hydrogen, and, when desired, converting a compound (I') obtained to a different compound (I'), and, when desired, converting an ester, amide or salt of a compound (I') to a corresponding free acid (I'), and, when desired, converting a free acid (I') to a corresponding pharmaceutically acceptable in vivo hydrolyzable functional derivative thereof at the carboxylic acid group selected from esters, amides and salts thereof.

2. A process according to claim 1 a) comprising reacting said bis-Grignard compound with said compound (III) in a molar ratio of 1 : 2.

3. A process according to claim 1 b) comprising reacting said compound (IV) with said ester (V) in a molar ratio of 1 : 2.

4. A process according to claim 1, wherein Q has 1 to 4 chain members part of a cyclohexyli-dene or phenylene ring.

5. A process according to claim 2, wherein Q has 1 to 4 chain members part of a cyclohexyli-dene or phenylene ring.

6. A process according to claim 3, wherein Q has 1 to 4 chain members part of a cyclohexyli-dene or phenylene ring.

:

7. A process according to claim 1 a) for preparing 1,4-phenylene-bis-[(1,1-dimethyl-but-4-yl)-dipropionic acid dimethyl ester]comprising reacting a bis-Gignard compound formed from 1,4-bis-(3-bromopropyl)-benzene with isopropyli-dene malonic acid diethyl ester.

8. A process according to claim 7 including a step of hydrolyzing the bis-dimethyl ester to product 1,4-phenylene-bis-[(1,1-dimethyl-but-4-yl)-dipropionic acid)].

9. A process according to claim 8 comprising heating the 1,4-phenylene-bis-[(1,1-dimethyl-but-4-yl)-dipropionic acid)] obtained in an inert atmosphere to effect rearrangement to form 1,4-phenylene -bis-(3,3-dimethyl-6-yl-hexanoic acid).

10. A process according to claim 1 (b) for preparing 1,4-phenylene-bis-(3,3-dimethyl-6-yl-5-hexenoic acid methyl ester comprising reacting 1,4-phenylene-bis-(methyltriphenyl-phosphonium chloride) with 3,3-dimethyl-5-oxopentanoic acid methyl ester.

11. A process according to claim 1 (b) for preparing 1,3-phenylene-bis-(3,3-dimethyl-6-yl-5-hexenoic acid methyl ester) comprising reacting 1,3-phenylene-bis-(methyltriphenyl-phosphonium chloride) with 3,3-dimethyl-5-oxo-pentanoic acid methyl ester.

12. A process according to claim 10 in-cluding a step of hydrogenating said hexenoic acid methyl ester to produce 1,4-phenylene-bis-(3,3-dimethyl-6-yl-hexanoic acid methyl ester).

13. A process according to claim 11 including a step of hydrogenating the hexenoic acid methyl ester to produce 1,3-phenylene-bis-(3,3-dimethyl-6-yl-hexanoic acid methyl ester).

14. A process according to claim 12 including a step of hydrolyzing said ester to produce 1,4-phenylene-bis-(3,3-dimethyl-6-yl-hexanoic acid).

15. A process according to claim 13 including a step of hydrolyzing said ester to produce 1,3-phenylene-bis-(3,3-dimethyl-6-yl-hexanoic acid).

16. A process according to claim 10 including a step of hydrolyzing said ester to produce 1,4-phenylene-bis-(3,3-dimethyl-6-yl-5-hexenoic acid).

17. A process according to claim 11 including a step of hydrolyzing said ester to produce 1,3-phenylene-bis-(3,3-dimethyl-6-yl-5-hexenoic acid).

18. A process according to claim 12 including a step of hydrogenating said ester to produce 1,4-cyclohexylidene-bis-(3,3-dimethyl-6-yl-hexanoic acid methyl ester).

19. A process according to claim 13 including a step of hydrogenating said ester to produce 1,3-cyclohexylidene-bis-(3,3-dimethyl-6-yl-hexanoic acid methyl ester).

20. A process according to claim 18 including a step of hydrolyzing said methyl ester to produce 1,4-cyclohexylidene-bis-(3,3-dimethyl-6-yl-hexanoic acid).

21. A process according to claim 19 including a step of hydrolyzing said methyl ester to produce 1,3-cyclohexylidene-bis-(3,3-dimethyl-6-yl-hexanoic acid).

22. A process according to claim 1(b) for pre-paring 1,4-phenylene-bis-(3,3-dimethyl-7-yl-5-heptenoic acid) comprising reacting 1,4-phenylene-bis-(ethyltriphenyl phosphonium bromide) wlth 3,3-dimethyl-5-oxo-pentanoic acid methyl ester.

23. A process according to claim 1(b) for preparing 1,3-phenylene-bis-(3,3-dimethyl-7-y]-5-heptenoic acid) comprising reacting 1,3-phenylene-bis-(ethyltriphenyl phosphonium bromide) with 3,3-dimethyl-5-oxo-pentanoic acid methyl ester.

24. A process according to claim 22 including a step of hydrogenating said heptenoic acid to produce 1,4-phenylene-bis-(3,3-dimethyl-7-yl-heptanoic acid).

25. A process according to claim 23 including a step of hydrogenating said heptenoic acid to produce 1,3-phenylene-bis-(3,3-dimethyl-7-yl-heptanoic acid).

26. A process according to claim 1 for preparing 1,4 cyclohexylidene-bis-(3,3-dimethyl-7-yl-heptanoic acid) comprising hydrogenating 1,4-phenylene-bis-(3,3-dimethyl-7-yl-heptanoic acid).

27. A process according to claim 1 for preparing 1,3-cyclohexylidene-bis-(3,3-dimethyl 7-yl-heptanoic acid) comprising hydrogenating 1,3-phenylene-bis-(3,3-dimethyl-7-yl-heptanoic acid).

28. A process according to claim 1 a) for preparing 1,4-phenylene-bis-(3,3-dimethyl-5-oxo-7-yl-heptanoic acid) comprising reacting a bis-Grignard compound formed from 1,4-bis-(2-bromo-methyl)-benzene with 3,3-dimethyl glutaric acid methyl ester chloride.

29. A process according to claim 28 including a step of reducing the heptanoic acid to produce 1,4-phenylene-bis-(3,3-dimethyl-7-yl-heptanoic acid).

30. A process according to claim 1, wherein R1 and R2 are both methyl, X and Y are both hydrogen and Q is a 1,4-phenylene-bis-(n-propyl) radical.

31. A process according to claim 1, wherein R1 and R2 are both methyl, X and Y are both hydrogen and Q is a 1,4-phenylene-bis-(allyl) radical.

32. An .alpha.,.omega.-dicarboxylic acid of formula (I'):

I' and in vivo hydrolyzable functional derivatives thereof at the carboxylic group, thereof in which R1 and R2 are the same or different and are selected from the group consisting of lower alkyl; lower alkyl substituted by a substituent selected from hydroxy, lower alkoxy, halogen, phenyl and phenyl itself substituted one or more times by a substi-tuent selected from hydroxy, lower alkoxy, lower alkyl or halogen; lower alkenyl; lower alkynyl;
C3 - C7 cycloalkyl; phenyl; phenyl substituted by a substituent selected from hydroxy, halogen, lower alkyl and lower alkoxy; X and Y, which may be the same or different, are selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, hydroxy, cyano, halogen, carboxyl, lower alkoxycarbonyl and carbamoyl, and Q is a linear, saturated or unsaturated alkylene chain of 8 to 14 carbon atoms, said alkylene chain being:
(a) unsubstituted or substituted by oxygen, halogen, hydroxy or lower alkoxy, (b) uninterrupted or interrupted by one or more heteroatoms, (c) completely uncyclized or having 1 - 4 chain members part of a C3 - C7 cycloalkyl or phenyl ring, provided that when Q is a linear saturated alkylene chain of 8 to 14 carbon atoms, R1 and R2 are both methyl and Y is hydrogen, X is other than hydrogen, ethoxycarbonyl, bromo, cyano or methyl, and provided that when R1 and R2 are both methyl and X and Y are both hydrogen, Q is other than a group of formula:

33. An .alpha.,.omega. -dicarboxylic acid of formula (I'), as defined in claim 32, wherein Q has 1 to 4 chain members part of a cyclohexylidene or phenylene ring.

34. 1,4-Phenylene-bis-[(1,1-dimethyl-but-4-yl)-dipropionic acid dimethyl ester].

35. 1,4-Phenylene-bis-[(1,1-dimethyl-but-4-yl)-dipropionic acid)].

36. An .alpha. ,.omega. -dicarboxylic acid of formula (I'), as defined in claim 32, wherein R1 and R2 are both methyl, X and Y are both hydrogen, and Q is a 1,3-phenylene-bis-(allyl) radical.

37. 1,4 Phenylene-bis-(3,3-dimethyl-6-yl-hexenoic acid).

38. 1,4-Phenylene-bis-(3,3-dimethyl-6-yl-5-hexenoic acid methyl ester).

39. 1,3-Phenylene-bis-(3,3-dimethyl-6-yl-5-hexenoic acid methyl ester).

40. 1,4-Phenylene-bis-(3,3-dimethyl-6-yl-hexenoic acid methyl ester).

41. 1,3-Phenylene-bis-(3,3-dimethyl-6-yl-hexenoic acid methyl ester).

42. 1,4-Phenylene-bis-(3,3-dimethyl-6-yl-hexenoic acid).

43. 1,3-Phenylene bis-(3,3-dimethyl-6-yl-hexenoic acid).

44. 1,4-Phenylene-bis-(3,3 dimethyl-6-yl-5-hexenoic acid).

45. 1,3-Phenylene-bis-(3,3-dimethyl-6-yl-5-hexenoic acid).

46. 1,4-Cyclohexylidene-bis-(3,3-dimethyl-6-yl-hexanoic acid methyl ester).

47. 1,3-Cyclohexylidene-bis-(3,3-dimethyl-6 yl-hexanoic acid methyl ester).

48. 1,4-Cyclohexylidene-bis-(3,3-dimethyl-6-yl-hexanoic acid).

49. 1,3-Cyclohexylidene-bis-(3,3-dimethyl-6-yl-hexanoic acid).

50. 1,4-Phenylene-bis-(3,3-dimethyl-7-yl-5-heptenoic acid).

51. 1,3-Phenylene-bis-(3,3-dimethyl-7-yl-5-heptenoic acid).

52. 1,4-Phenylene-bis-(3,3-dimethyl-7-yl-heptanoic acid).

53. 1,3-Phenylene-bis-(3,3-dimethyl-7-yl-heptanoic acid).

54. 1,4-Cyclohexylidene-bis-(3,3-dimethyl-7-yl-heptanoic acid).

55. 1,3-Cyclohexylidene-bis-(3,3-dimethyl-7-yl-heptanoic acid).

56. 1,4-Phenylene-bis-(3,3-dimethyl-5-oxo-7-yl-heptanoic acid).

57. An .alpha., .omega. -dicarboxylic acid of formula (I'), as defined in claim 1, wherein R1 and R2 are both methyl, X and Y are both hydrogen and Q is a 1,4-phenylene-bis-(n-propyl) radical.

58. A process according to claim 1, wherein R1 and R2 each independently represents methyl, ethyl, hydroxymethyl or phenyl, and X and Y each independently represents hydrogen, halogen, methody, hydroxy, cyano, ethoxycarbonyl, carbamoyl or carboxyl.

59. A process according to claim 1, wherein R1 and R2 each represent methyl, Y represents hydrogen and X represents hydrogen, halogen, methoxy, cyano, ethoxycarbonyl, carbamoyl or carboxyl.

60. A process according to claim 1, wherein R1 and R2 represent methyl and X and Y represent hydrogen.

61. A process according to claim 1, wherein Q represents the -(CH2)n-cyclohexylidene-(CH2)n, -(CH2)m-phenylene-(CH2)m-, -CH2-CH = CH - phenylene -CH2 = CH-CH2, or -CH2-CH = CH-CH2-phenylene-CH2-CH = CH-CH2 -and n is 2, 3 or 4 and m 3 or 4.

62. A process according to claim 1, including recovering an in vivo hydrolyzable functional derivative of the carbaoxylic groups which is a salt with a pharmacologically acceptable alkali:
metal, alkaline earth metal or ammonium bases;
ester with a lower alcohol, amide with ammonia or a lower alkylamine or lactone.

63. A pharmaceutical composition for the treat-ment of obesity, hyperlipidemeia or diabetes com-prising as active ingredient an effective amount of an .alpha., .omega. -dicarboxylic acid of formula (I') as defined in claim 32, 33 or 36, or a pharmaceuti-cally acceptable in vivo hydrolyzable functional derivative thereof at the carboxylic acid group selected from salts, amides and esters thereof, in association with a pharmaceutically acceptable carrier therefor.

64. A pharmaceutical composition for the treatment of obesity, hyperlipidemia or diabetes comprising as active ingredient an effective amount of a compound as defined in claim 34, 35 or 37, in association with a pharmaceutically acceptable carrier therefor.

65. A pharmaceutical composition for the treatment of obesity, hyperlipidemia or diabetes comprising as active ingredient an effective amount of a compound as defined in claim 38, 39 or 40, in association with a pharmaceutically acceptable carrier therefor.

66. A pharmaceutical composition for the treatment of obesity, hyperlipidemia or diabetes comprising as active ingredient an effective amount of a compound as defined in claim 41, 42 or 43, in association with a pharmaceutically acceptable carrier therefor.

67. A pharmaceutical composition for the treatment of obesity, hyperlipidemia or diabetes comprising as active ingredient an effective amount of a compound as defined in claim 44, 45 or 46, in association with a pharmaceutically acceptable carrier therefor.

68. A pharmaceutical composition for the treatment of obesity, hyperlipidemia or diabetes comprising as active ingredient an effective amount of a compound as defined in claim 47, 48 or 49, in association with a pharmaceutically acceptable carrier therefor.

69. A pharmaceutical composition for the treatment of obesity, hyperlipidemia or diabetes comprising as active ingredient an effective amount of a compound as defined in claim 50, 51 or 52, in association with a pharmaceutically acceptable carrier therefor.

70. A pharmaceutical composition for the treatment of obesity, hyperlipidemia or diabetes comprising as active ingredient an effective amount of a compound as defined in claim 53, 54 or 55, in association with a pharmaceutically acceptable carrier therefor.

71. A pharmaceutical composition for the treatment of obesity, hyperlipidemia or diabetes comprising as active ingredient an effective amount of a compound as defined in claim 56 or 57, in association with a pharmaceutically acceptable carrier therefor.